PPAR (peroxisome proliferator activated receptor) refers to an intranuclear receptor whose ligand is a peroxisome proliferator, a compound capable of increasing the number of peroxisome. Also, it is known that PPAR has three isoforms of PPARα, PPARδ and PPARγ (J Steroid Biochem. Molec. Biol., 51, 157, 1994; Gene Expression, 4, 281, 1995; Biochem. Biophys. Res. Commun., 224, 431, 1996).
PPAR mainly controls expression of genes participating in fat metabolism or genes participating in differentiation of adipocytes (J. Invest. Dermatol. 111, 1116-1121, 1998; J. Med. Chem., 43, 527-550, 2000). Among the above PPAR isoforms, PPARα is expressed mainly in the liver, the retina and the adipose tissue, and participates in oxidation of fatty acids, neutralization of toxic materials, or inflammatory reactions. PPARγ is expressed mainly in the adipocytes, the immune cells, the adrenal gland, the spleen and the small intestine, and is known to function as a central mediator in the differentiation of adipocytes. PPARδ is not expressed in a tissue-specific manner but expressed broadly, and the function of PPARδ is not clearly understood (Endocrinology., 137, 354, 1996).
Because PPAR has an important role in fat metabolism, many studies have been conducted to develop a medicine for treating metabolic diseases in which PPAR is involved. It is known that when PPARα is activated, expression of enzymes increasing fatty acid decomposition and decreasing fatty acid synthesis in the liver increases, thereby decreasing synthesis of triglycerides and production and secretion of VLDL (very low density lipoprotein). It is also known that activation of PPARα result in activation of LPL (lipoprotein lipase), and reduced production of apoC-III which is inducing generation of VLDL (Curr. Pharm Des., 3: 1-14, 1997). Additionally, it is known that fibrate, known as a ligand of PPARα, reduces triglycerides by 20-50%, and reduces LDL while increasing HDL (Atherosclerosis, 171: 1-13, 2003). Therefore, ligands of PPARα are useful for treating obesity, dyslipidemia and cardiovascular diseases caused by accumulation of triglycerides (Curr. Opin. Lipidol., 10: 245-257, 1999).
In addition, activation of PPARγ causes maximization of sugar receptability of adipocytes, stimulates differentiation of adipocytes and reduces insulin resistance (Tren. Pharmacol. Sci., 25:331-336, 2004). Therefore, ligands of PPARγ can act as medicine for treating non-insulin-dependent diabetes mellitus (Type 2 diabetes mellitus) caused by insulin resistance. Currently, TZD pharmaceuticals such as pioglitazone and rosiglitazone, which are typical ligands of PPARγ, are used as medicines for treating non-insulin-dependent diabetes mellitus.
As mentioned above, since PPAR is a target in the treatment of metabolic diseases including diabetes, diabetic complications, or the like, many attempts have been made to date to develop PPAR ligands for activating PPAR. U.S. Pat. No. 6,939,875 discloses a composition useful for treating PPAR-mediated diseases. It is also disclosed that the composition of U.S. Pat. No. 6,939,875 is effective for treating non-insulin-dependent diabetes mellitus, obesity, eating disorders, appetite suppressing, leptin level modulation, and metabolic syndrome. Additionally, U.S. Pat. No. 6,967,212 discloses a composition comprising a substituted azole acid derivative acting as a PPAR agonist. It is also disclosed that the composition of U.S. Pat. No. 6,967,212 is effective for treating insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, syndrome X, dysmetabolic syndrome, inflammation, diabetic complications, impaired glucose homeostasis, impaired glucose tolerance, hypertriglyceridemia or atherosclerosis. Further, other substances effective for treating various PPAR-mediated diseases are disclosed (U.S. Pat. Nos. 6,930,120, 7,041,691 and 7,037,914).
However, PPAR ligands that have been known to date cause side effects such as liver toxicity, hypoglycemic conditions and obesity. Hence, it is required to develop a ligand capable of activating PPAR from a natural source that causes low side effects such as toxicity. Nevertheless, there have been few studies to develop a ligand capable of activating PPAR from a natural source.
Meanwhile, Myristica fragrans is a perennial plant cultivated in the tropics. Fruits of Myristica fragrans, known as mace or nutmeg, have been used as spice for a long time. Macelignan is a typical lignan-based compound, which is found in Myristica fragrans (Phytochemistry, 59: 169-17, 2002). It is reported that macelignan has the functions of enhanced activity of caspase-3 inducing apoptosis (Biol. Pharm. Bull., 27: 1305-1307, 2004), an antibacterial effect against oral microorganisms (Korean Laid-Open Patent No. 10-2005-0035954), inhibited peroxidation of cerebral cell lipids and inhibited production of active oxygen (Biochem. Biophys. Res. Commu., 331: 1264-1269), or the like. However, any studies of the interrelation between macelignan and PPAR have not yet been reported.